Effects of computerized cognitive training on biomarker responses in older adults with mild cognitive impairment: A scoping review

Abstract Background and Aims Mild cognitive impairment (MCI) is a widespread condition in older individuals, posing significant risk of dementia. However, limited research has been conducted to explore effective interventions and clarify their impact at the neural level. Therefore, this study aimed to investigate the effects of computerized cognitive training (CCT) and explore the associated neural mechanisms in preventing dementia in older individuals with MCI, with a view to inform future intervention efforts. Methods We reviewed the effects of CCT on biomarker outcomes in older adults with MCI. The search was conducted for studies published between 2010 and May 10, 2023, using three search engines: PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature. The inclusion criteria were as follows: studies that involved participants diagnosed with MCI, included CCT, included quantitative assessment of biomarker results, and conducted randomized controlled trials. Results Sixteen studies that used biomarkers, including magnetic resonance imaging, electroencephalography (EEG), functional near‐infrared spectroscopy (fNIRS), and blood or salivary biomarkers, were extracted. The results showed that CCT caused changes in structure and function within the main brain network, including the default mode network, and decreased both theta rhythm activity on EEG and prefrontal activity on fNIRS, with improvement in cognitive function. Furthermore, CCT combined with physical exercise showed more significant structural and functional changes in extensive brain regions compared with CCT alone. Virtual reality‐based cognitive training improved not only executive function but also instrumental activities of daily living. Conclusion CCT causes functional and structural changes in extensive brain regions and improves cognitive function in older adults with MCI. Our findings highlight the potential of individualized intervention methods and biomarker assessment according to the specific causes of MCI. Future research should aim to optimize these personalized therapeutic strategies to maximize the benefits of CCT in older adults with MCI.

potential of individualized intervention methods and biomarker assessment according to the specific causes of MCI.Future research should aim to optimize these personalized therapeutic strategies to maximize the benefits of CCT in older adults with MCI.

| INTRODUCTION
Mild cognitive impairment (MCI) is characterized by a decline in cognitive function, but it typically preserves intellectual and daily life skills in older individuals. 1The incidence rate of MCI ranges from 15% to 20% in older adults aged ≥65 years, 2 with Alzheimer's disease (AD) being the most common cause of MCI. 1 MCI is considered a prodromal stage of dementia, with the condition progressing to dementia in 4%-22% of cases and reverting to normal cognition in 20%-57% of cases over 4 years. 3Early interventions at the MCI stage are important for preventing dementia; however, no pharmacotherapy has been established for preventing progression to dementia.
5][6][7][8] Although these interventions are recommended to prevent dementia in older individuals with MCI, it is difficult for these individuals to continue training after intervention cessation. 7Hence, intervention methods that allow participants to continue training without difficulty are required.
With rapid advancements in computer science over the past decade, computerized cognitive training (CCT) using virtual reality (VR) and information and communication technology (ICT) has been increasingly used to prevent dementia in older individuals with MCI. 9,10Furthermore, mandatory social distancing due to the coronavirus disease pandemic has facilitated CCT using ICT. 11CCT is structured, and previous studies have reported the use of the Cognitive Operations Gear COG Pack (COGPACK), 12 Cogmed Working Memory Training Program, 13 and Comprehensive and Complex Cognitive Stimulation Program. 14CCT has been considered a flexible and convenient method to delay cognitive decline, as CCT programs have reportedly improved cognitive function in older individuals with MCI, 15,16 and the effects of CCT are comparable to those of conventional cognitive training. 17Moreover, CCT includes games that use commercially available game software, such as the Xbox 360 Kinect and VR technology, which provide sensory feedback through auditory, visual, and tactile stimulation. 18These training programs allow participants to continue the training safely and enjoyably. 19[22][23][24] Nevertheless, although several research groups have demonstrated improvements in cognitive function due to CCT, only a few studies have examined the neural mechanism of the effects of CCT on cognitive function in older adults with MCI.Recently, the number of studies using biomarkers to estimate the effects of CCT in older adults with MCI has gradually increased, and the following effects have been reported: elevation of serum brain-derived neurotrophic factor (BDNF) level 25 ; recovery of increased delta and theta bands on electroencephalography (EEG) 21 ; increased gray matter volume, 26 cerebral blood flow, or brain metabolism 27,28 ; and enhanced functional connectivity (FC) in neural networks. 29Moreover, the effect on biomarkers after intervention differs depending on CCT content and the presence or absence of a combination of physical exercises. 12,17,25,29though a previous review demonstrated the effects of CCT on neuroimaging outcomes in older adults in 2017, it included healthy older adults and limited biomarkers for neuroimaging. 30To the best of our knowledge, no review has focused on biomarkers for investigating the effects of CCT in older adults with MCI.Therefore, this study aimed to review the findings of biomarker assessments for evaluating the effects of CCT, to understand the underlying neural mechanism of CCT in preventing dementia in older individuals with MCI, and to provide directions for future intervention efforts.

Key points
• Computerized cognitive training (CCT) causes functional and structural changes in extensive brain regions in older adults with mild cognitive impairment (MCI), with improvement in cognitive function.
• The effect of CCT combined with physical exercise may be stronger and longer-lasting than that of CCT alone.
• Virtual reality-based cognitive training may improve not only executive function but also instrumental activities of daily living.
or "Single Photon Emission Computed Tomography" or "Positron Emission Tomography" or "electroencephalography" or "saliva" or "blood" or "serum" or "plasma" or "cerebrospinal fluid") and ("digital" or "virtual reality" or "computerized" or "computer" or "exergame" or "robot" or "telemedicine" or "Artificial Intelligence" or "Information and Communication Technology").Two researchers (HH and ST) independently conducted the initial search of the databases by reading all the abstracts of the articles generated to confirm that they targeted computerized training and biomarkers in older adults with MCI.The entire texts of the extracted studies were then reviewed against the inclusion criteria.The researchers held discussions when they disagreed with their respective judgments on the criteria.We also used snowball sampling for the reference lists of relevant articles.Study citations were imported into a reference management software (EndNote 20, Clarivate Analytics) for selection.

| Literature search findings
Based on a search of the three databases, 3513 studies were identified in the initial search, of which 553 duplicates and 116 reviews were removed.Of the three search engines used, the initial search results in PubMed are shown in supplementary material 1.

Articles that did not target interventions for MCI, computerized
training, or assessment of biomarkers (n = 2805) were excluded.The entire text of 39 articles was read by two researchers, and 13 articles that met the inclusion criteria were selected.Additionally, three studies were included after screening the references of relevant reviews.Finally, 16 studies were selected for analysis (Figure 1).The characteristics of the studies are presented in Table 1.

| Biomarkers assessed in the included studies
The 16 extracted RCT studies were divided into five categories: (1)   structural magnetic resonance imaging (MRI), ( 2) functional MRI, ( EEG, (4) functional near-infrared spectroscopy (fNIRS), and (5) serum and salivary biomarkers.All the studies estimated the correlations between biomarkers and cognitive functional outcomes.

| Structural MRI (n = 4)
Four studies reported volumetric and cortical thickness outcomes A task-based MRI study revealed that participants in the CCT group, with CCT, conducted 100 min/day, 5 days per week for 2 months, showed higher hippocampal activation with improvement in verbal memory than participants in the control group. 41sting-state fMRI (rsfMRI) had shown significantly enhanced FC between the hippocampus and superior frontal cortex, with attenuation of memory decline in the CCT group after intervention with the COGPACK program. 12In a study involving an online

| Electroencephalography (EEG) (n = 3)
A study using the Xbox 360 Kinect CCT program for 25-30 min, five times per week for 6 weeks, showed significantly lower delta waves and complex EEG with improvements in attention, executive function, and global cognitive function in the intervention group than in the control group. 38In another two studies conducted by the same research group, the VR-based cognitive training (VRCT) group (100 min, 3 times/week for 8 weeks) showed significantly lower theta/beta ratio in the temporal and parietal regions with improvements in executive function compared with the control group. 19,32A comparison between the VRCT and exercise groups showed significantly lower theta power in the parietal area and lower connectivity in the PFC, ACC, and temporal and parietal regions in the VRCT group than in the exercise group. 32.7 | Functional near-infrared spectroscopy (fNIRS) (n = 2) Two studies used fNIRS as a biomarker. 17 compared with that noted in the control group. 25

| DISCUSSION
We included 16 studies and reviewed the types and findings of biomarkers to evaluate the effects of CCT in older adults with MCI.
The biomarkers extracted in our study included MRI, EEG, fNIRS, and serum and salivary biomarkers.

| MRI
Among the articles extracted in our study, MRI was the most frequently used.As two of the four structural MRI studies also examined connectivity within cerebral regions, we have discussed structural and functional MRI together.CCT enhances regional activity in areas of the hippocampus related to improvement in verbal memory 41 and in the temporal poles and insular cortices, which are related to improvement in global cognitive function, attention, memory, visuospatial configuration, and executive function. 39It also enhances regional activity in the ACC and superior frontal cortex, leading to improved attention, memory, and global cognitive function. 33Regarding the FC between brain regions, CCT enhanced the FC between the hippocampus and superior frontal cortex related to improvement in memory, 12 between the hippocampus and PCC, 37 between the frontal and occipital regions related to improvements in the RCFT copy task, 9 and between the DMN and SLN with improvement in overall cognitive function. 29These studies have focused on structural and functional changes within major brain networks, such as the DMN, executive control network (ECN), and SLN.Furthermore, changes in these major brain networks by CCT were investigated.
The main brain regions involved in the DMN are the PCC, medial PFC, ACC, and inferior parietal lobule. 42In particular, the PCC, which plays a vital role in the DMN, receives input from several regions, including the hippocampus, and engages in cognitive functions such as memory, attention, and visuospatial cognition. 43The FC between the PCC and hippocampus is attenuated from the MCI stage due to AD. 44 Possible reasons for the efficacy of CCT in older patients with MCI include the recovery of weakened FC between the PCC and hippocampus, enhancement of FC within the DMN, and an increase in FC between the DMN and other major brain networks, including the SLN. 29,37e ECN is composed of the DLPFC, ventrolateral PFC, and PCC 45 and plays crucial roles in the integration of sensory and memory information, the regulation of cognition and behavior, and the WM process with the prefrontal lobe. 46Imaging biomarkers in MCI include changes in specific brain regions in the ECN, primarily the precuneus, cuneiform nucleus, lingual gyrus, middle frontal gyrus, and PCC. 47The improvement in cognitive function, including executive function, by CCT may be related to an increase in the volume of the DLPFC, which is a component of the ECN, and the PCC, which is a component common to the ECN and DMN. 12,40other major brain network, i.e., the SLN, primarily comprises the insula and dorsal ACC, which participate in attention and switching between cognitive resources. 48The SLN is significantly affected in patients with MCI, 49 and specific functional alterations in the SLN and interactions of the SLN with the DMN in MCI may be useful as potential imaging biomarkers for MCI. 50One possible reason for the efficacy of CCT in older patients with MCI is the enhanced regional activity in the insula and ACC. 29,33,39wever, some studies have reported contradictory results in these contexts.For example, studies have reported no structural change after WM training 35 or enhanced FC in the neural network after CCT involving non-crossword puzzles. 29Another study demonstrated that FC changes in the PCC negatively correlated with improvement in delayed memory. 33One possible reason for these results is the diversity of MCI.Cognitive function and MRI findings following CCT may differ according to the cause of MCI, such as AD or Lewy body disease, and in the early and late stages of MCI. 29 The second reason may be associated with a compensatory mechanism.
FC within the DMN increases as a compensatory mechanism to maintain cognitive function in MCI due to AD. 51 CCT can help in recovering the increased FC within the brain network after improvement in cognitive function.Other potential reasons may be related to the dose and duration of CCT.A greater exercise dose is positively correlated with increased PFC and ACC volumes. 40A certain dose and duration of CCT may be required for certain changes to be evident using MRI.Furthermore, analysis of genes related to the maintenance of neural function revealed that MRI findings after training differed depending on gene polymorphisms. 35us, investigating the genetic polymorphisms associated with neural function may be important for predicting the effects of training.

| EEG
Previous EEG studies in patients with MCI revealed consistent neural alterations compared to those in healthy adults, involving decreased alpha and beta rhythm activities, increased delta and theta power band activities, 52 and decreased EEG complexity. 53eta waves increase because of the slower axonal conduction time in subcortical areas. 54Slower and less complex EEG patterns are caused by damage to cholinergic neurons in the lateral capsular and perisylvian pathways, which play important roles in cortical activity. 53,55In our study, EEG was reported to significantly decrease theta rhythm activity in the temporal and parietal regions after CCT. 19,32These studies suggest that CCT can help recover damaged cholinergic neurons in extensive brain regions, leading to improvements in attention, executive function, and global cognitive function. 19,32,383 | fNIRS fNIRS can measure alterations in the hemoglobin concentration on the cortical surface in response to neuronal activity.56 Hemodynamic data revealed significantly decreased activation in the prefrontal areas after training in VR-trained participants, 17 which is consistent with the result of a previous study.57 In MCI, compensatory functions are activated, and the activity of a wide range of neural networks increases to maintain brain function.58 When cognitive training stimulates neuronal plasticity, the burden on neural activity during task is reduced, resulting in less active neural networks.57,59,60 Changes in prefrontal activation on fNIRS after the intervention may be a biomarker for estimating the effects of CCT.In the studies analyzed herein, 16-or 8-channel fNIRS was used to assess hemodynamic data in the PFC.fNIRS using more multichannel, for example, 54-channel fNIRS, may be required to evaluate activation in all brain regions. trining.25,62 In contrast, Quialheiro et al. 14 reported that increased BDNF levels, which reflect a compensatory mechanism in MCI, decreased after interventions.However, it may be difficult to evaluate the intervention effects at the BDNF level in older adults with MCI.
Growth factors of the VEGF family play an important role in the protection and recovery from ischemia by regulating angiogenesis. 63RNAs in circulating exosomes play a key role in neurodegenerative diseases, such as AD, affecting several processes involved in disease pathology. 64VEGF and miRNA levels decrease in neurodegenerative diseases and may increase postexercise, 65,66 making them potential biomarkers to investigate intervention effects.However, few studies have investigated these as biomarkers of intervention effects in older adults with MCI, and further studies are required.

| Drop-out rates in the included studies
All studies extracted in this study mentioned drop out.Drop-out rates varied from 0% 29,36 to 87% 40 in the intervention groups in this study, possibly influenced by cognitive function 39 and motivation 67 in the subjects, and duration of the intervention 67 as has been reported by other authors. 39,67This finding underscores the importance of recognizing that CCT programs may not necessarily allow participants to continue training without difficulty.Thus, CCT programs that consider the interests, cognitive abilities, and physical function of older adults with MCI are warranted.

| Combined intervention and virtual realitybased cognitive training
In our study, 8 of the 16 studies included were conducted using combined CCT and physical exercise.A meta-analysis of RCTs demonstrated that the combination of CCT and physical exercise had positive effects on cognitive function, including executive function and attention, compared with the effects of CCT alone. 68In our study, CCT showed significantly lesser atrophy in the PCC in the physical exercise group than in the CCT alone group, 12 and MRI performed 12 months after training cessation showed significantly enhanced FC between the hippocampus and PCC than in the CCT alone group. 37Given the results of these studies using biomarkers, combined interventions may be more effective and longer-lasting than CCT alone.

35 3. 5 |
after interventions.Suo et al. 12 divided participants into four groups: CCT (COGPACK program) + progressive resistance training (PRT), sham CCT + PRT, CCT+sham PRT, and double sham.Both the CCT and PRT consisted of sessions lasting 90 min/day, 2 days/week, for 26 weeks.The results showed a significant increase in cortical thickness in the posterior cingulate cortex (PCC) with improvement in global function in the CCT + PRT group and attenuated decline in overall memory performance with no volumetric change in the CCT group.Twelve months after training cessation, the atrophy rates in the left hippocampus were significantly slower in the PRT + CCTgroup than in the double sham group.37Anderson-Hanley et al.40 conducted mental and physical exercises, starting with a minimum of 20 min at least twice a week and gradually increasing the exercise duration to 45 min and frequency to at least three to five times a week for 3 months and maintained that pattern through a 6-month period.The results showed a significant improvement in executive function, and exercise dose was associated with increased gray matter volume in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC).In addition, a significant improvement in memory was associated with increased gray matter volume in the dorsal lateral PFC (DLPFC).In another study, CCT performed at home using the Cogmed working memory (WM) training program revealed no structural cortical changes after the intervention; the training was conducted for 30-40 min, five times/week for 5 weeks.However, the results revealed significantly increased cortical thickness in the right frontal superior region and right paracentral region in Lim homeobox transcription factor-alpha (LMX1A)-AA carriers of the LMX1A polymorphism, associated with the maintenance of dopaminergic neurons and disorders, such as Parkinson's disease.Functional MRI (fMRI) (n = 7) CCT program at the patient's home for 120-160 min/week with 3-4 sessions per week for 6 months, rsfMRI showed significantly increased regional activity at the bilateral temporal poles, insula cortices, and hippocampus with improvement in Mini-Mental State Examination score, attention, memory, visuospatial configuration, and executive function.However, training effects were not significant 12 months after the last training.39Another follow-up study conducted 12 months after intervention cessation by Suo et al. found significantly enhanced FC between the hippocampus and PCC, with no long-term cognitive improvement in the CCT + PRT group.37In a VR-based cognitive training session that was conducted for 20-30 min, twice per week for 4 weeks, rsfMRI revealed significantly increased FC between the frontal and occipital regions associated with improvement in the Rey-Osterrieth Complex Figure Test (RCFT) score. 9A rsfMRI study on computerized crossword training for four 30-min per week sessions for 12 weeks and subsequent booster training until 72 weeks showed significantly enhanced FC within the default mode network (DMN) and FC between the DMN and salience network (SLN) with improvement in the 11-item Alzheimer's Disease Assessment Scale-Cognitive total score.29,34Another rsfMRI study using the Remote Expressive Arts Program for 60 min, twice weekly for 12 weeks, found significantly increased activation in the right ACC and left dorsolateral superior frontal gyrus related to improved attention, memory, and global cognitive function.33

36 3. 8 |
,36 Compared with VRbased physical and cognitive training (VR training: physical training for 40 min, cognitive training for 20 min, 3 times/week for 12 weeks) and combined physical and cognitive training (60 min, 3 times/week for 12 weeks), the results showed significantly decreased activation in the prefrontal areas after training in both groups and an improvement in global cognitive function, verbal memory, and instrumental activities of daily living (IADLs) in only the VR training group. 17Another study compared cognitive-physical dual-task training (40 min, twice/week for 8 weeks) with only executive function training (40 min, twice/week for 8 weeks).Compared with the single cognitive task, the cognitive-physical dual-task training showed significantly better executive process and lower prefrontal activity during cognitive testing, but no significant differences were noted in IADLs between the groups.Serum or salivary biomarkers (n = 3) The comprehensive and complex cognitive stimulation program consisted of 120 min of computer activity, physical activity, and exchanging experiences in a conversation circle two times/week for 12 weeks.The intervention showed significantly decreased serum BDNF levels with improvement in global cognitive function but with no significant change in serum S100 calcium-binding protein B or neuron-specific enolase levels. 14Aerobic and cognitive exercises (mentioned before) significantly increased salivary BDNF, vascular endothelial growth factor (VEGF), and exosomal microRNA-9 (miRNA-9) expressions, with improvement in memory and executive function after intervention. 40In another study, participants were randomized into four groups: physical training; mental training, that is, CCT (30-60 min, 3 times/week for 8 weeks); combined training; and control.The results showed a significant increase in serum BDNF levels in the mental training group, with improvements in WM

4. 4 |
Blood or salivary biomarkers BDNF, VEGF, and miRNAs are biomarkers that are measurable using blood or saliva.Our results indicate that post-intervention BDNF levels increased or decreased, with contradictory results.BDNF belongs to the family of neurotrophic proteins, is important for the normal development of the central and peripheral nervous systems, and plays a prominent role in the development, survival, and function of neurons.61BDNF is a central biomarker of neuroplasticity, and several studies have shown increased BDNF levels after physical or cognitive

1
Study flowchart.RCT, randomized controlled trial.Details of randomized controlled trials on the effects of computerized cognitive training on biomarker responses in older adults with mild cognitive impairment. 14 36